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PLoS One. 2017 Dec 7;12(12):e0188168. doi: 10.1371/journal.pone.0188168. eCollection 2017.

Copy number variants in Ebstein anomaly.

Author information

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America.
Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America.
Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa, United States of America.
Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York, United States of America.
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
California University of California San Francisco School of Medicine, San Francisco, California, United States of America.
Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.



Ebstein anomaly (EA) is a rare congenital defect characterized by apical displacement of the septal tricuspid leaflets and atrialization of the right ventricle. The etiology of EA is unclear; however, recurrence in families and the association of EA with genetic syndromes and copy number variants (CNVs) suggest a genetic component.


We performed a population-based study to search for recurrent and novel CNVs in a previously unreported set of EA cases.


We genotyped 60 EA cases identified from all live births (2,891,076) from selected California counties (1991-2010) using the Illumina HumanOmni2.5-8 array. We identified 38 candidate CNVs in 28 (46%) cases and prioritized and validated 11 CNVs based on the genes included.


Five CNVs (41%) overlapped or were close to genes involved in early myocardial development, including NODAL, PDLIM5, SIX1, ASF1A and FGF12. We also replicated a previous association of EA with CNVs at 1p34.1 and AKAP12. Finally, we identified four CNVs overlapping or in close proximity to the transcription factors HES3, TRIM71, CUX1 and EIF4EBP2.


This study supports the relationship of genetic factors to EA and demonstrates that defects in cardiomyocytes and myocardium differentiation may play a role. Abnormal differentiation of cardiomyocytes and how genetic factors contribute should be examined for their association with EA.

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